期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 80, 期 -, 页码 308-315出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.04.071
关键词
Molecular imaging; Positron emission tomography; Integrin alpha(v)beta(3); Copper-64; Bifunctional chelator (BFC); Imaging; Diagnosis; Prognosis
资金
- Prostate Cancer Research Program of the United States Army Medical Research and Materiel Command [W81XWH-08-1-0305, W81XWH-12-1-0336]
It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the alpha(v)beta(3) integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the alpha(v)beta(3) integrin (106, 108, 85 and 100 nM for rac-H-2-1, RR-H-2-1, SS-H-2-1, and RS-H-2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 +/- 0.45, 2.60 +/- 0.52, 2.45 +/- 0.48 and 2.88 +/- 0.59 for rac-Cu-64-1, RR-Cu-64-1, SS-Cu-64-1, and RS-Cu-64-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 +/- 0.21, 2.13 +/- 0.58, 1.70 +/- 0.20 and 1.90 +/- 0.46 %ID/g at 24 h p.i. in liver for rac-Cu-64-1, RR-Cu-64-1, SS-Cu-64-1, and RS-Cu-64-1 respectively; 1.80 +/- 0.46, 2.30 +/- 1.49, 1.73 +/- 0.31 and 2.23 +/- 0.71 at 24 h p.i. in kidneys for rac-Cu-64-1, RR-Cu-64-1, SS-Cu-64-1, and RS-Cu-64-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in alpha(v)beta(3)-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents. (C) 2014 Elsevier Masson SAS. All rights reserved.
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